These mice exhibit a molecular and progressive neurodegenerative phenotype similar to Type III spinal muscular atrophy.
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Hung Li, Institute of Molecular Biology
Genetic Background | Generation |
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N10F30
|
Allele Type | Gene Symbol | Gene Name |
---|---|---|
Targeted (Null/Knockout) | Smn1 | survival motor neuron 1 |
Allele Type |
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Transgenic (Inserted expressed sequence, Humanized sequence) |
Starting at:
$255.00 Domestic price for female 4-week |
510.00 Domestic price for breeder pair |
Mice that are homozygous for the Smn1tm1Hung knock-out allele and homozygous for the Tg(SMN2)2Hung transgene display a varied Type III SMA phenotype - they are viable, fertile and exhibit short and thickened tails. RT-PCR analysis detects alternative splicing of the transgene. Histological examination of tail tissue reveals atrophic muscles and subcutaneous edema. Skeletal muscle tissue has fewer myocytes and atrophic muscle bundles. Large motor neurons in the anterior horns of the spinal cord degenerate and are lost. There is a strong correlation between estimated copy number of the transgene and severity of the neurodegenerative phenotype. Of note, mice hemizygous for Tg(SMN2)2Hung have ~2 copies of the transgene, whereas mice homozygous for Tg(SMN2)2Hung have ~4 copies of the transgene.
Mice homozygous for Smn1tm1Hung and hemizygous for Tg(SMN2)2Hung display a Type I SMA-like phenotype and die at ~14 days of age.
Mice that are heterozygous for Smn1tm1Hung and hemizygous for Tg(SMN2)2Hung are phenotypically normal.
Non-transgenic (noncarrier) mice are phenotypically normal when heterozygous for Smn1tm1Hung, but embryonic lethal when homozygous for Smn1tm1Hung - failing to survive past embryonic day 6.5.
Importation of this model was supported by the Spinal Muscular Atrophy Foundation.
Double mutant mice were generated by crossing transgenic mice carrying the human SMN2 gene with mice heterozygous for the Smntm1Hung targeted mutation.
The targeted mutant allele was generated by disrupting exon 7 with a vector containing neomycin resistance and herpes simplex virus thymidine kinase genes. This construct was electroporated into 129P2/OlaHsd-derived E14TG2a embryonic stem cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts and chimeric animals obtained. Chimeric animals were crossed to C57BL/6 for more than 5 generations.
The transgene consists of 115 kb of sequence from the SMN BAC clone 7C, including the entire human SMN2 coding region and flanking sequence. The transgenic construct was microinjected into male pronuclei of FVB/N mice. Founder line 2 (hemizygotes) were determined to have ~2 copies of the transgene. Founder line 2 was crossed to mice heterozygous for the targeted mutation, Smntm1Hung. The double mutant was then backcrossed to FVB/N for five generations.
Expressed Gene | SMN2, survival of motor neuron 2, centromeric, human |
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Site of Expression |
Allele Name | targeted mutation 1, Hung Li |
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Allele Type | Targeted (Null/Knockout) |
Allele Synonym(s) | Smn-; Smndelta 7 |
Gene Symbol and Name | Smn1, survival motor neuron 1 |
Gene Synonym(s) | |
Strain of Origin | 129P2/OlaHsd |
Chromosome | 13 |
General Note | Homozygous mutant mice died during the peri-implantation stage. In contrast, homozygous mutant mice carrying Tg(SMN2)1Hung display pathological changes in the spinal cord and skeletal muscles similar to those of patients with proximal spinal muscular atrophy (SMA). Some of these mice do not develop hairy fur, and die before postnatal day 10. Others exhibit poor activity and variable symptoms, and die at approximately 2-4 weeks. A third group of these mice survive to adulthood and are fertile, but have short enlarged tails. The variable severity of the pathological changes in these mice correlates with transgene copy number and the amount of protein that contains the region encoded by exon 7. |
Molecular Note | Exon 7 was replaced with an HPRT cassette via homologous recombination. Homozygous embryos were detected at E3.5 but not after E6.5. |
Mutations Made By | Hung Li, Institute of Molecular Biology |
Allele Name | transgene insertion 2, Hung Li |
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Allele Type | Transgenic (Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | SMN2+ |
Gene Symbol and Name | Tg(SMN2)2Hung, transgene insertion 2, Hung Li |
Gene Synonym(s) | |
Promoter | SMN2, survival of motor neuron 2, centromeric, human |
Expressed Gene | SMN2, survival of motor neuron 2, centromeric, human |
Strain of Origin | FVB/N |
Chromosome | UN |
General Note | Five lines were generated. Hemizygous transgenic mice that are also homozygous for Smn1tm1Hung display:
|
Molecular Note | The transgene consists of 115kb of sequence from the SMN BAC clone 7C, including the entire human SMN2 coding region and flanking sequence. Five lines were generated. |
Mutations Made By | Hung Li, Institute of Molecular Biology |
The Smn1 (survival motor neuron 1) gene on Chr 13 and the randomly inserted transgene are not linked and will segregate independently.
Mice homozygous for the Smn1tm1Hung knock-out allele and homozygous for the Tg(SMN2)2Hung transgene (double homozygous mice) are viable and fertile with a varied Type III SMA phenotype. The Jackson Laboratory Stock No. 005058 is routinely maintained by breeding double homozygous mice together [i.e., breeding HOM HOM x HOM HOM].
Of note, breeding double homozygous mice from Stock No. 005058 to mice from the Smn1tm1Hung heterozygous non-transgenic control line (Stock No. 031678) would allow researchers to generate the following offspring:
i. homozygous for Smn1tm1Hung and hemizygous for Tg(SMN2)2Hung [i.e., HOM HEMI; ~50%] - these mice display a Type I SMA-like phenotype and die at ~14 days of age
ii. heterozygous for Smn1tm1Hung and hemizygous for Tg(SMN2)2Hung [i.e., HET HEMI; ~50%] - these mice are phenotypically normal
When using the SMA-like mouse strain in a publication, please cite the originating article(s) and include JAX stock #005058 in your Materials and Methods section.
Service/Product | Description | Price |
---|---|---|
Hemizygous or Non carrier for Tg(SMN2)2Hung,Heterozygous or Wild-type for Smn1<tm1Hung> |
Frozen Mouse Embryo | FVB.Cg-Smn1<tm1Hung> Tg(SMN2)2Hung/J Frozen Embryos | $2595.00 |
Frozen Mouse Embryo | FVB.Cg-Smn1<tm1Hung> Tg(SMN2)2Hung/J Frozen Embryos | $2595.00 |
Frozen Mouse Embryo | FVB.Cg-Smn1<tm1Hung> Tg(SMN2)2Hung/J Frozen Embryos | $3373.50 |
Frozen Mouse Embryo | FVB.Cg-Smn1<tm1Hung> Tg(SMN2)2Hung/J Frozen Embryos | $3373.50 |
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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.
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